KV7.2 channel dysfunction delays neuronal maturation and undermines early network development in a hiPSC model of KCNQ2-DEE

KCNQ2 developmental and epileptic encephalopathy ( KCNQ -DEE), is caused predominantly by dominant-negative loss-of-function variants in the KCNQ2 gene, leading to neonatal-onset epileptic seizures and profound neurodevelopmental impairment. Using patient induced pluripotent stem cells (iPSC)-derived neurons and complementary murine model, we found that dominant-negative KCNQ2 variants leading to diminished M-current cause depolarized resting membrane potential, reduced action potential generation and fragmented early network oscillations, all indicative of delayed neuronal development. These effects were most pronounced at immature developmental stages and replicated by pharmacological M-current inhibition, highlighting a critical role for Kv7.2 during early neuronal maturation. Notably, our data challenge the prevailing view that KCNQ2 -DEE symptoms are solely driven by hyperexcitability. Instead, we reveal a biphasic pattern in which loss of M-current delays the acquisition of basic functional properties in developing neurons, with potential consequences for synaptogenesis and cortical circuit formation. These findings provide a plausible cellular mechanism for the early-onset developmental delay observed in KCNQ2 -DEE patients, even when seizures are effectively controlled. They raise the possibility that seizure-suppressing therapies such as carbamazepine may disrupt the development of immature networks, but further work is needed to assess clinical relevance. • The pathogenesis of KCNQ2 -DEE begins during prenatal development with variant effects depending on maturation stage • M-current dysfunction delays neuronal maturation before the onset of hyperexcitability. • Early patient-derived neurons show impaired action potential generation and network activity. • Synchronized oscillations, a marker of advanced neuronal maturity, are underdeveloped in patient neurons. • Carbamazepine impacts early network activity with potential developmental implications, but further work is needed to assess clinical relevance.